Ehrlichioses and anaplasmoses are caused by alpha-proteobacteria within thefamily of Anaplasmataceae. These diseases have been known for a long time inveterinary medicine and recently in human medicine. These tick-borne zoonosesare considered as emerging diseases. The first case of human monocytotropicehrlichiosis occurred in 1986. Human granulocytic anaplasmosis was described asa separate entity in 1994 and ehrlichiosis caused by Ehrlichia ewingii wasreported in humans in 1999. The number of cases has been rising steadily due tobetter diagnostic techniques and better surveillance worldwide. In this review,we will present human and animal ehrlichioses and anaplasmoses as emergingdiseases and present candidate(s) for the future.

We examined 198 questing Ixodes ricinus ticks collected in Chisinau City, Republic of Moldova by PCR assays for Anaplasma phagocytophilum, Borrelia burgdorferi sensu lato and co-infection of both pathogens, which were detected in 9%, 25.2% and 2.5% of tested ticks, respectively. B. burgdorferi s.l. genotyping revealed the presence of five genospecies with dominance of B. garinii. Our preliminary study provides evidence about occurrence of both pathogens in this populated area, which represent a potential health risk for inhabitants.

Anaplasma phagocytophilum, Ehrlichia chaffeensis and Ehrlichia ewingii are emerging tick-borne pathogens and are the causative agents of human granulocytic anaplasmosis, human monocytic ehrlichiosis and E. ewingii ehrlichiosis, respectively. Collectively, these are referred to as human ehrlichioses. These obligate intracellular bacterial pathogens of the family Anaplasmataceae are transmitted by Ixodes spp. or Amblyomma americanum ticks and infect peripherally circulating leukocytes to cause infections that range in clinical spectra from asymptomatic seroconversion to mild, severe or, in rare instances, fatal disease. This review describes: the ecology of each pathogen; the epidemiology, clinical signs and symptoms of the human diseases that each causes; the choice methods for diagnosing and treating human ehrlichioses; recommendations for patient management; and is concluded with suggestions for potential future research.

Background: Lyme disease (LD), babesiosis, and human granulocytic ehrlichiosis (HGE) are emergent zoonotic diseases affecting residents in the Northeastern and Midwestern United States. The etiologic agents of each disease are perpetuated in a natural cycle between vertebrate reservoir hosts and the tick vector, Ixodes scapularis. The geographical and ecological over-lap between HGE, LD and babesiosis suggests the potential for co-transmission, co-infection and co-morbidity. We describe the case of a Connecticut resident simultaneously infected with all three agents.

Case Report: A previously healthy, 23 year-old male presented to an emergency department (ED) after five days of headache, fever, sweats, myalgia, and fatigue. He recalled a tick bite about one week earlier. He was given the diagnosis of LD and treated with clarithromycin. Approximately two weeks later, the symptoms returned and he presented to our ED. Laboratory evaluation revealed leukopenia, thrombocytopenia, and a hematocrit of 41%. Liver function tests, and erythrocyte sedimentation rate were normal. LD serologies were sent. On evaluation, he was found to have tonsillar, cervical, and inguinal lymphadenopathy and splenomegaly that was confirmed by abdominal CT scan. Five days later, the patient returned to the ED with acute left upper quadrant pain, and persistent fevers. Hematocrit was 29%. Repeat abdominal CT scan demonstrated increased splenomegaly and new left flank and pelvic fluid. The patient was admitted to the surgical intensive care unit with the presumed diagnosis of splenic rupture. Laboratory data were significant for leukopenia, thrombocytopenia, elevated LDH and AST, and decreased haptoglobin. The hospital course was remarkable for persistent high-grade fevers to 104.6° F. Lymph node biopsy showed follicular lymphoid hyperplasia and no evidence for malignancy. A peripheral smear showed intraerythrocytic ring forms 54 consistent with Babesia. The patient was treated with clindamycin and quinine with rapid defervescence. LD serologies from the previous ED visit were positive on both ELISA and Western Blot. After completing a course of clindamycin and quinine, the patient was started on a course of doxycycline. Serum samples were sent for HGE and Babesia microti serology. Indirect fluorescent antibody staining methods revealed an HGE titer of 1:4096 and a B. microti titer of 1:640. HGE-specific ELISA was confirmatory. Nine months later, repeat testing demonstrated a >4-fold decrease in antibody titer to both HGE and B. microti.

Conclusion: This patient had concurrent infection with three I. scapularis-borne diseases. The unexpected severity of illness in this otherwise healthy host can in part be attributed to the delay in diagnosis resulting from an atypical presentation and the possible immunosuppressive effects resulting from the interplay of the three diseases.

Department of Infectious Diseases & Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA.

The use of new, highly sensitive diagnostic methods has revealed persistent infections to be a common feature of different tick-borne diseases, such as babesiosis, anaplasmosis and heartwater. Antigenic variation can contribute to disease persistence through the continual elaboration of new surface structures, and we know in several instances how this is achieved. Known or suspected mechanisms of persistence in babesial parasites include cytoadhesion and rapid variation of the adhesive ligand in Babesia bovis and genetic diversity in several merozoite stage proteins of different Babesia spp. In Anaplasma, extensive variation in the pfam01617 gene family accompanies cycling of organism levels in chronic infection. One result from the pioneering research at Onderstepoort is the definition of a related polymorphic gene family that is likely involved in immunity against heartwater disease. We are beginning to understand the sizes of the antigenic repertoires and full definition is close, with the possibility of applying simultaneous high-throughput sequencing to the order of 1000 small genomes. We also, for the first time, can consider modifying these genomes and looking at effects on persistence and virulence. However, important biological questions remain unanswered; for example, why we are seeing a new emerging Anaplasma infection of humans and is infection of endothelial cells by Anaplasma significant to persistence in vivo.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt
University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee.

Ehrlichiosis, a tickborne illness transmitted by tick vectors Amblyomma americanum and Ixodes scapularis, can be acquired in endemic areas. Clinical manifestations range from asymptomatic to fulminant in nature. We report three cases of ehrlichiosis in pediatric oncology patients, one of whom was a stem cell transplant recipient. Early symptoms included fever, malaise, and vague gastrointestinal symptoms. Laboratory abnormalities were initially attributed to chemotherapy toxicity. Illness was severe in all three patients and one patient died even after initiation of doxycycline. These cases emphasize the need for a high index of suspicion for tickborne illness in oncology patients, and the importance of a low threshold for starting empiric treatment before confirming the diagnosis.

Anaplasma spp. and Ehrlichia spp. cause several emerging human infectious diseases. Anaplasma phagocytophilum and Ehrlichia chaffeensis are transmitted between mammals by blood-sucking ticks and replicate inside mammalian white blood cells and tick salivary-gland and midgut cells. Adaptation to a life in eukaryotic cells and transmission between hosts has been assisted by the deletion of many genes that are present in the genomes of free-living bacteria (including genes required for the biosynthesis of lipopolysaccharide and peptidoglycan), by the acquisition of a cholesterol uptake pathway and by the expansion of the repertoire of genes encoding the outer-membrane porins and type IV secretion system. Here, I review the specialized properties and other adaptations of these intracellular bacteria.

Human ehrlichiosis and anaplasmosis are acute febrile tick-borne diseases caused
by various members of the genera Ehrlichia and Anaplasma (Anaplasmataceae).
Human monocytotropic ehrlichiosis has become one of the most prevalent
life-threatening tick-borne disease in the United States. Ehrlichiosis and
anaplasmosis are becoming more frequently diagnosed as the cause of human
infections, as animal reservoirs and tick vectors have increased in number and
humans have inhabited areas where reservoir and tick populations are high.
Ehrlichia chaffeensis, the etiologic agent of human monocytotropic ehrlichiosis
(HME), is an emerging zoonosis that causes clinical manifestations ranging from
a mild febrile illness to a fulminant disease characterized by multiorgan system
failure. Anaplasma phagocytophilum causes human granulocytotropic anaplasmosis
(HGA), previously known as human granulocytotropic ehrlichiosis. This article
reviews recent advances in the understanding of ehrlichial diseases related to
microbiology, epidemiology, diagnosis, pathogenesis, immunity, and treatment of
the 2 prevalent tick-borne diseases found in the United States, HME and HGA.
2010 Elsevier Inc. All rights reserved.

Human ehrlichiosis is the term for a collection of tick-borne diseases caused
primarily by obligate intracellular bacteria of the Ehrlichia species.
Ehrlichiosis is characterized by a mild to severe illness, with approximately
3-5% of cases proving fatal despite receiving appropriate care. This report
presents the case of a 60 year-old woman who was found collapsed and
unresponsive in her home after an indeterminate time; possibly for up to 48 h.
Despite rigorous resuscitative care and antibiotic treatment, the patient lapsed
into multi-organ failure and died. Subsequent analysis by microscopic
examination, PCR and immunohistochemistry revealed the patient died from an
infection of Ehrlichia chaffeensis. Clinicians and pathologists must be aware of
this emergent disease in order to make a timely and appropriate diagnosis.
Discussion of the patient's clinical, laboratory and autopsy findings as well as
treatment of Ehrlichia chaffeensis infections is presented.

Molecular and cellular pathobiology of Ehrlichia infection: targets for new
therapeutics and immunomodulation strategies.

McBride JW, Walker DH.

Department of Pathology, Center for Emerging Infectious Diseases and Biodefense,
Sealy Center for Vaccine Development, and the Institute for Human Infections and
Immunity, University of Texas Medical Branch, Galveston, TX, USA.

Ehrlichia are small obligately intracellular bacteria in the order Rickettsiales
that are transmitted by ticks and associated with emerging life-threatening
human zoonoses. Vaccines are not available for human ehrlichiosis, and
therapeutic options are limited to a single antibiotic class. New technologies
for exploring host-pathogen interactions have yielded recent advances in
understanding the molecular interactions between Ehrlichia and the eukaryotic
host cell and identified new targets for therapeutic and vaccine development,
including those that target pathogen virulence mechanisms or disrupt the
processes associated with ehrlichial effector proteins. Animal models have also
provided insight into immunopathological mechanisms that contribute
significantly to understanding severe disease manifestations, which should lead
to the development of immunomodulatory approaches for treating patients nearing
or experiencing severe disease states. In this review, we discuss the recent
advances in our understanding of molecular and cellular pathobiology and the
immunobiology of Ehrlichia infection. We identify new molecular host-pathogen
interactions that can be targets of new therapeutics, and discuss prospects for
treating the immunological dysregulation during acute infection that leads to
life-threatening complications.

Two children presented with a history of fever and rash. Lab values revealed
pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both
children quickly developed respiratory distress and hypotension requiring
admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies
for Ehrlichia returned positive. The patients were started on doxycycline and
treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery.
In both patients, testing for MUNC and perforin genes were found to have no
mutation. These two cases demonstrate the importance of considering Ehrlichiosis
as a possible trigger of HLH. Pediatr Blood Cancer 2011;56:661-663. (c) 2010
Wiley-Liss, Inc. Copyright (c) 2010 Wiley-Liss, Inc.

Human granulocytic anaplasmosis (HGA) is a tick-borne rickettsial infection of neutrophils caused by Anaplasma phagocytophilum. Although the pathogen was known as a veterinary agent as early as 1932, the link with human disease was first established in 1990. In the past decennium, the involvement of HGA as an important and frequent cause of fever with a history of tick bite was increasingly recognized in many regions of Europe.

This paper presents a 10-year A. phagocytophilum serosurveillance (2000-2009), wherein 1672 serum samples were tested and 418 were found positive. A total of 111 patients had a history of tick bite, fever, and at least a 4-fold rise in titre and are thus considered to be confirmed cases.
These findings suggest that Belgium is a hot spot for HGA infections.

[Serology of Lyme borreliosis and human granulocytic ehrlichiosis in 2005-2010].

Balátová P, Kurzová Z, Hulínská D

Epidemiol Mikrobiol Imunol 2011 06; 60 (2): 74-6

The subject of this study is serological screening of blood and CSF (cerebrospinal fluid) samples for the presence of borrelial and ehrlichial antibodies. A total of 165 patients suspected to be at risk of Lyme disease were tested. Indirect immunofluorescence and enzyme immunoassay were used as diagnostic methods. Ehrlichial antibodies were detected in 36 (21.8%) patients. Borrelial antibodies were found in 70 samples (42.4%). The widening range of tick-borne diseases brings about the need for more data on these zoonoses.

Ehrlichiosis is the multiorgan infectious disease caused by small, intracellular rickettsias from the genus Ehrlichia. These microorganisms are known as an etiologic factor of infections world wide in humans and in different species of animals. Dog ehrlichiosis can be caused by several species of Ehrlichia attacking different groups of blood cells, but most often an infection by Ehrlichia canis is diagnosed with special relation to monocytes. A vector for E. canis are Rhipicephalus sanguineus and Ixodes ricinus, commonly occurring in Poland. Disease caused by E. canis is known as Canine Monocytic Ehrlichiosis (CME). The disease most often has an asymptomatic course which can, in favourable circumstances, run into acute or chronic forms. The acute form of CME proceeds usually with fever, apathy, weakness and accompanying respiratory symptoms, lameness and disturbances in blood coagulation. In laboratory examinations thrombocytopenia, anemia and leucopenia are ascertained. Th e chronic form of CME proceeds among gentle, unspecific symptoms which may last even 5 years. The CME diagnosis is difficult and often demands parallel different diagnostic methods. A medicines of choice in the ehrlichiosis treatment are antibiotics from the group of tetracyclines, given at least for 28 days. They are largely efficient during treatment of the acute CME, causing the quick improvement. Instead, in the case of chronic form, answer for treatment can be weak, and cases of resistance to antibiotics ave known.

Human granulocytic anaplasmosis (HGA) is a tick-borne infection characterised by an acute, nonspecific febrile illness. To date, few clinical cases have been supported by both a positive polymerase chain reaction (PCR) assay and subsequent seroconversion against Anaplasma phagocytophilum antigen all over Europe. We report here 3 consecutive cases of HGA that occurred during the summer of 2009 which fulfilled the epidemiologic, clinical, and biological criteria for HGA. These data highlight PCR assay on ethylenediaminetetraacetic acid blood rather than serology as the diagnostic test of choice during the acute phase of the disease. In endemic areas, HGA should be investigated in patients presenting an undifferentiated febrile illness with cytopenia, elevated rates of liver enzymes, and increased C-reactive protein values.

Location: From the Blood Bank and Transfusion Medicine, the Division of Infectious Disease, The Miriam Hospital, and the Rhode Island Blood Center, Providence, Rhode Island; and Imugen, Inc., Norwood, Massachusetts.

DOI: 10.1111/j.1537-2995.2012.03685.x

BACKGROUND: Human granulocytic anaplasmosis (HGA) is a tick-borne rickettsial infectious disease. To date four cases of transfusion-transmitted anaplasmosis (TTA) have been described in the literature, and only one from leukoreduced red blood cells (RBCs).

CASE REPORT: A 64-year-old patient with acute gastrointestinal blood loss was admitted to the hospital and received 5 units of prestorage leukoreduced RBCs. He was stabilized and discharged. He developed headache, fever, and chills 2 days after discharge and was readmitted. On Day 5 of his second admission polymorphonuclear leukocytes containing morulae consistent with HGA were reported in the peripheral smear.

RESULTS: Samples from the recipient tested positive by polymerase chain reaction (PCR) for Anaplasma phagocytophilum, the causative agent of HGA and a segment from one of the five donors tested positive by both serology and PCR.

J Ark Med Soc. 2013 Jun;109(13):280-2.Ehrlichiosis presenting with toxic shock-like syndrome and secondary hemophagocytic lymphohistiocytosis.Pandey R, Kochar R, Kemp S, Rotaru D, Shah SV.SourceDepartment of Internal Medicine, University of Arkansas for Medical Sciences Little Rock, AR, USA.AbstractHuman monocytotropic ehrlichios is a tick borne illness caused by Ehrlichia chaffeensis. Ehrlichiosis presenting with septic shock and severe azotemia is rare, and may be seen in immunocompromised individuals. We present a case of ehrlichia induced toxic shock like syndrome in a patient with rheumatoid arthritis on disease modifying agents. He also had oliguric renal failure requiring dialysis on presentation and later found to have Hemophagocytic Lymphohistiocytosis secondary to severe ehrlichia sepsis.